The DFCI-based ALL Consortia consist of a 9-institution pediatric group and 8-institution adult group. The pediatric consortium has conducted multi-institutional trials since 1981, whereas the adult program began in 2003 with the initiation of a pilot/feasibility protocol for patients >18-50 years old. Upon completion of the adult pilot in 2005, we propose to initiate a common adult/pediatric clinical trial for patients age 1-50 years with de novo ALL, as well as to enroll patients with relapsed or refractory ALL in studies testing agents discovered and screened in Projects 1-5 in the context of "investigational windows". Our pediatric consortium has a well-established record of successfully conducting randomized clinical trials and performing detailed studies of chemotherapeutic pharmacokinetics, acute morbidities, and late effects, all in the context of extremely favorable event-free survival outcomes. Our clinical trials of newly diagnosed ALL have a common treatment philosophy based on intensive early therapy, with research focused on minimizing toxicities without compromising efficacy. In childhood ALL, we have demonstrated differences in cytotoxicity, pharmacokinetics, toxicity and efficacy of various asparaginase preparations. We have also made fundamental contributions to the characterization and prevention of doxorubicin cardiotoxicity and late occurring neuropsychological toxicity, and have extensively evaluated quantitative measures of quality of life outcomes. In addition to clinical trials in newly diagnosed patients (ages 1-50 years), we are committed to developing novel therapies, and continuing our investigations into the pathogenesis of ALL , as well as chemical genomic markers of disease variability and potential targets for future therapy. The combined pediatric and adult consortia will provide approximately 180 patients per year, thus enabling the unique age-unrestricted clinical and laboratory studies described in Projects 1-6.